Date of Award

5-2016

Degree Type

Dissertation

Degree Name

Doctor of Philosophy

Major

Biomedical Engineering

Major Professor

Zannatul Ferdous

Committee Members

Roberto S. Benson, Deidra J. Mountain, Shanfeng Wang

Abstract

Calcific Aortic Valve Disease (CAVD) is a major disorder in the developed countries among elderly. It is characterized by calcific deposition and stiffening of the aortic valve cusps. CAVD is a highly cell-mediated condition where valvular interstitial cells (VICs) become activated and differentiate into osteoblast-like cells. This is associated with upregulation of calcific markers like Alkaline phosphatase (ALP) and Runx2. ECM remodeling in another characteristic of stenotic aortic valves due to VIC activation. Reports show that CAVD initiates majorly on the noncoronary side of the aortic valves. Additionally, male sex is a significant risk factor of CAVD. Aortic valves are surrounded by a complicated hemodynamic environment. Pathological levels of mechanical forces applied to the aortic cusps interact with the VICs’ remodeling and differentiation and lead to abnormalities within the aortic cusps.

In this dissertation, comparative studies were performed among VICs isolated from individual aortic cusps or between male and female to verify whether the differences in aortic calcification are observed at a cellular level. The calcification of VICs isolated from coronary and noncoronary aortic cusps was investigated in osteogenic culture condition to identify whether VICs show different amounts of calcific markers. Moreover, the osteogenic differentiation of VICs isolated separately from male and female aortic valves was analyzed to find if there are sex-related differences in their proliferation and calcification. Finally, both hypotheses were tested under cyclic strain to determine the impact of pathological vs. physiological strain on enhancing the VICs calcification among coronary and noncoronary cusps or between male and female valves. It was found that VICs isolated from noncoronary cusps demonstrated greater calcification potential than coronary cusps. Likewise, male VICs showed increased ECM remodeling compared to female. Pathological cyclic strain applied to VICs cultured in osteogenic condition enhanced their calcification, however VICs cultured in normal condition seem not to be affected by pathological cyclic strain.

The results from this dissertation provide a new perspective on the biomolecular events associated with VICs calcification. It shows that VICs in different cusps of an aortic valve have heterogeneous populations. Furthermore, it confirms that sex of the cells matter in aortic valve calcification.

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